Neurochemical signals in brain are rapidly terminated by several processes, including transporters. Neurotransporters on cell surface membranes decrease the availability of neurotransmitters by sequestering them into neurons or glia for storage processing or metabolism. Drugs that bind to transporters generally increase synaptic neurotransmitter availability by blocking transport. The transporters for the monoamines dopamine, serotonin and norepinephrine are principal targets for the majority of antidepressant drugs, methylphenidate (Ritalin), the most frequently prescribed drug for Attention Deficit Hyperactivity Disorder, and cocaine. By blocking monoamine transporters and elevating monoamine levels the drugs trigger a cascade of biochemical events, leading to therapeutic benefit, or in the case of cocaine, stimulate effects and abuse liability. Without exception, the molecular structure of therapeutic and other drugs that modulate monoamine transporters contains an amine nitrogen. Drug design has been guided by a prevailing but untested premise that drugs require an amine nitrogen, corresponding to the amine nitrogen of neurotransmitters, to bind a counterion on the transporter protein. We recently discovered several compounds without an amine nitrogen, aryloxatropanes (8-oxa-bicyclo-3-aryl-[3.2.1.]octanes), that are potent inhibitors of the dopamine serotonin and/or norepinephrine transporters in monkey brain. We extended this series to other novel nonamines in order to investigate structure-activity relationships. 1. In this series the oxytropane was linked to an aromatic ring in the position. We demonstrated stereoselective binding of the most potent representative compounds ((1R)O-1072 3.27 nM vs (1S)O-1114 47nM). 2. We demonstrated significant influence of halogens on the aromatic ring of these derivatives. In this regard the rank order of potency of halogenated derivatives was 3,4-Cl2 > I > Cl > Br > F >>H. 3. Selectivity of this series of compounds for the dopamine over the serotonin transporter was low. 4. If the aromatic ring was substituted in the 3 position, the compounds displayed similar stereoselectivity but greater selectivity for the dopamine over the serotonin transporter. These results indicate that a number of nonamines are potent inhibitors of the dopamine and serotonin transporters, and similar in potency to their amine nitrogen bearing counterparts. The results demonstrate that an amine nitrogen is not essential for blockade of monoamine transporters. Within this series, transporter affinity appears to be largely sustained by the aromatic ring. Orientation of the 3-aryl moiety influences transporter selectivity. Based on these results, transporter-inhibitor association may be guided by aromatic ring interactions. Future research will investigate the pharmacological activity of these compounds and structure-activity relationships with a view of developing a model of the monoamine transporter. This research will clarify the feasibility of developing cocaine antagonists for the dopamine transporter. Meltzer PC, Liang AY, Gonzalez MD, Blundell P, Madras BK. The first synthesis of 2-carbomethoxy-3-aryl-8-oxabicyclo[3.2.1]octanes;